The Safety of Methimazole and Propylthiouracil in Pregnancy: A Systematic Review

Drugs in Pregnancy
MOTHERISK ROUNDS
The Safety of Methimazole and Propylthiouracil
in Pregnancy: A Systematic Review
Rinat Hackmon, MD,1,2 Monica Blichowski, BSc,1,2 Gideon Koren, MD1,2
1
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto ON
2
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto ON
Abstract
Résumé
Background: Hyperthyroidism is one of the most common endocrine
disorders in pregnant women, and it can severely complicate
the course and outcome of pregnancy. Methimazole (MMI) and
propylthiouracil (PTU) are the standard anti-thyroid drugs used in
the treatment of hyperthyroidism in pregnancy. Traditionally, MMI
has been considered to have clearer evidence of teratogenicity
than PTU. Recent studies suggest that PTU can be hepatotoxic,
leading to a United States Food and Drug Administration “black
box alert.” We wished to systematically review the effects of PTU
and MMI during pregnancy, and to compare maternal and fetal
safety.
Contexte : L’hyperthyroïdie est l’un des troubles endocriniens les
plus courants chez les femmes enceintes et peut gravement
compliquer l’évolution et l’issue de la grossesse. Le méthimazole
(MMI) et le propylthiouracile (PTU) sont les antithyroïdiens
standard qui sont utilisés dans la prise en charge de
l’hyperthyroïdie pendant la grossesse. Traditionnellement, le MMI
a été considéré comme présentant des signes de tératogénicité
plus manifestes que le PTU. Des études récentes laissent
entendre que le PTU peut être hépatotoxique, ce qui a mené à
la publication d’un encadré (« black box alert ») à ce sujet par
la Food and Drug Administration américaine. Nous souhaitions
procéder à l’analyse systématique des effets du PTU et du MMI
pendant la grossesse, ainsi qu’à la comparaison de leur innocuité
chez la mère et le fœtus.
Methods: We conducted a systematic search of PubMed, EMBASE,
TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google.
Both English and non-English publications were included. We
excluded studies using anti-thyroid therapies other than PTU and
MMI, studies not allowing interpretation of results, and abstracts of
meetings.
Results: Overall, insufficient statistical power precluded
determination of accurate rates of either MMI teratogenicity or
PTU hepatotoxicity in cohort studies. However, a case–control
study helped identify the relative risk of MMI-induced choanal
atresia. A second case–control study failed to show that aplasia
cutis congenita is associated with MMI. PTU has been associated
with a rare but serious form of hepatic failure.
Conclusion: MMI causes a specific pattern of rare teratogenic
effects after first trimester exposure, while PTU therapy may be
followed by rare but severe hepatotoxic sequelae. It is therefore
appropriate to use PTU to treat maternal hyperthyroidism during
the first trimester of pregnancy, and to switch to MMI for the
remainder of the pregnancy.
Méthodes : Nous avons mené des recherches systématiques dans
PubMed, EMBASE, TOXNET, TOXLINK, DART, Medscape,
EBSCO et Google. Les documents publiés tant en anglais que
dans d’autres langues ont été inclus. Nous avons exclu les études
faisant appel à d’autres antithyroïdiens que le PTU et le MMI,
les études ne permettant pas l’interprétation des résultats et les
résumés de réunions.
Résultats : De façon globale, l’insuffisance de la puissance
statistique a empêché la détermination de taux précis pour ce
qui est de la tératogénicité du MMI ou de l’hépatotoxicité du PTU
dans les études de cohorte. Toutefois, une étude cas-témoins a
contribué à identifier le risque relatif d’atrésie choanale attribuable
au MMI. Une deuxième étude cas-témoins n’est pas parvenue à
démontrer que l’aplasie ectodermique congénitale était associée
au MMI. Le PTU a été associé à une forme rare mais grave
d’insuffisance hépatique.
Conclusion : Le MMI cause un ensemble particulier d’effets
tératogènes rares à la suite d’une exposition au cours du premier
trimestre, tandis que le traitement au PTU peut donner lieu à
des séquelles hépatotoxiques rares mais graves. Il s’avère
donc approprié d’utiliser le PTU pour la prise en charge de
l’hyperthyroïdie maternelle au cours du premier trimestre de
la grossesse, pour ensuite passer au MMI pour le reste de la
grossesse.
Key Words: Propylthiouracil, methimazole, birth defects,
hyperthyroidism, pregnancy
Competing Interests: None declared.
J Obstet Gynaecol Can 2012;34(11):1077–1086
NOVEMBER JOGC NOVEMBRE 2012 l 1077
Drugs in Pregnancy
INTRODUCTION
H
yperthyroidism is one of the most common
endocrine disorders in pregnant women and can
severely complicate the course and outcome of pregnancy.
It is characterized by excessive secretion by the thyroid of
tri-iodothyronine and thyroxine.1 The most common cause
of hyperthyroidism is Graves’ disease, an organ-specific
autoimmune disorder that is mediated by thyroid stimulatory
immunoglobulins.2 These autoantibodies mimic the action
of thyroid stimulating hormone, leading to increased
thyroid function. The diagnosis of hyperthyroidism is made
when serum thyroid stimulating hormone is depressed and
serum free T4 and the free thyroxin index are elevated.3
Treatment options include anti-thyroid drugs, surgical
resection of the thyroid, symptomatic relief (e.g., betablockers), and/or radiotherapy.4
In pregnant women, the incidence of hyperthyroidism is
0.2% to 0.3%,2,5–9 and Graves’ disease accounts for 85%
of cases.10,11 Left untreated, hyperthyroidism poses serious
risks for both fetus and mother,9 including preeclampsia,
thyroid storm, heart failure, miscarriage and stillbirth,
prematurity, intrauterine growth restriction, and neonatal
thyrotoxicosis.3
Favourable fetal and maternal outcomes require control
of the mother’s abnormal thyroid function.3 The amides
propylthiouracil and methimazole are thyroid peroxidase
analogues, capable of reducing the synthesis of T3 and
T4 while also blocking iodine release. The goal of therapy
with these agents is to maintain the mother’s serum free T4
concentration in the high to normal range using the lowest
possible drug dose.12 Both drugs readily cross the placenta
with similar kinetics of placental transfer.13
PTU has been considered the drug of choice during pregnancy,
mostly because MMI has been associated with characteristic
teratogenic effects including aplasia cutis congenita, choanal
atresia, tracheoesophageal fistulas, and other less common
abnormalities.1 ACC is a localized absence of skin in the
occipital area of the scalp, usually ranging in size from 0.3
to 5 cm.14 Rarely, the lesion may extend below the scalp and
ABBREVIATIONS
ACC aplasia cutis congenita CA choanal atresia
FDA United States Food and Drug Administration
MMI methimazole
PTU propylthiouracil
T3 tri-iodothyronine
T4 thyroxine
1078 l NOVEMBER JOGC NOVEMBRE 2012
include absent skull bone and dura; in this case, surgical
intervention is required. The incidence of ACC ranges from
0.03% to 0.05% (0.6 to 1 per 2000 births).14
CA is a rare obstruction of the posterior choanae with
an incidence of approximately 0.01% to 0.05% (1 to 5
per 10 000 births).15,16 The obstruction can be unilateral
or bilateral, bony or membranous.7 In cases of bilateral
obstruction, surgical intervention is required.
In addition, MMI has been also associated with the
following anomalies:
1. facial abnormalities including broad forehead, broad
nasal bridge, arched eyebrows15
2. hypoplastic nipples7
3. gastrointestinal manifestations such as esophageal
atresia and tracheoesophageal fistula17
4. growth restriction and delayed development.5,14,17,18
While ACC is the more common malformation associated
with MMI, it has mostly benign implications, while CA and
other features of the embryopathy have greater clinical
effects on the newborn.
Although several studies have supported an association
between MMI therapy and ACC, CA, and tracheoesophageal
fistulas,7,16 others have failed to show such associations.19,20
Traditionally, PTU has been considered a superior choice
for treatment in pregnant women because it has not been
associated with teratogenicity. However, unlike MMI, few
studies of PTU teratogenicity have been published.14
During the last two decades a growing number of reports
have raised concerns about PTU-induced hepatotoxicity.21
This has led to the issuing of a black box warning by the
Food and Drug Administration in the United States. Only
sporadic cases reporting liver toxicity following treatment
of PTU during pregnancy have been reported.21
The objective of the present study was to systematically
review the relevant literature in order to assess the maternal
and fetal risks of treatment with MMI and PTU during
pregnancy and provide clarifications for evidence-based
treatment of gestational hyperthyroidism.
METHODS
The following electronic databases were searched: Ovid
Medline (articles published from 1948 to March 2012),
EMBASE (articles published from 1947 to March 2012),
The Safety of Methimazole and Propylthiouracil in Pregnancy: A Systematic Review
Flow chart of selected studies
Total number of records identified: 2468
Ovid MEDLINE (1270)
TOXNET (1068)
MEDSCAPE (130)
Number of records excluded: 2167
Excluded due to not being relevant
Number of records screened: 301
Number of records excluded: 270
The remaining excluded articles were
review papers
Number of records included: 31
and TOXNET, TOKLINK, Medscape, EBSCO, and
Google, with no restrictions on language or year of
publication. The last search was run on March 15, 2012.
Our search strategy included the following MeSH terms:
“methimazole” and/or “propylthiouracil” combined
with “pregnancy,” “pregnancy adverse outcome” or
“malformations” or “cutis aplasia” or “choanal atresia”
or “embryopathy” or “hepatitis.” The search was limited
further to human data and clinical trials. Reference lists of
relevant review papers and all selected articles were handsearched to identify additional trials.
Exclusion criteria were (1) studies including anti-thyroid
therapies other than PTU and MMI; and (2) studies with
insufficient data to allow interpretation of results.
RESULTS
A total of 2468 publications were identified. After applying
the exclusion criteria, 31 publications were reviewed
to evaluate the adverse effects of MMI or PTU. These
included cohort and case–control studies and case reports
or case series (Figure). No RCTs were identified.
Methimazole
Cohort studies
Several retrospective cohort studies addressed MMI
teratogenicity , and only a few of these studies evaluating
MMI teratogenicity identified cases with one of the features
associated with fetal MMI.19–20,22–24 Di Gianantonio et al.
conducted a multicentre cohort study of MMI-associated
malformations after intrauterine exposure to MMI and
carbimazole.22 This study identified 241 infants who were
exposed to MMI and carbimazole in utero and reported one
case of CA and one of esophageal atresia in the exposed
group. The authors concluded that these malformations
might have a higher than expected incidence in fetuses
exposed to MMI and carbimazole between three and seven
weeks’ gestation.22
NOVEMBER JOGC NOVEMBRE 2012 l 1079
Drugs in Pregnancy
In a study with a similar sample size, Momotani et al.
identified 243 women exposed to MMI during the first
trimester of pregnancy and found no such anomalies.19 In
this comparative study, other unrelated adverse anomalies
were reported, including one case of omphalocele and
one ear lobe abnormality. Overall, there were significantly
fewer malformations in the MMI-exposed group than
in a comparison group of women with untreated
hyperthyroidism. In a cohort study by Mujtaba and Burrow,
two cases of ACC were identified among 15 newborns
exposed prenatally to MMI.23 In another cohort, two mild
cases of ACC were reported among 15 newborns exposed
prenatally to MMI.24
with ACC, 12 with CA, and three with other features of
MMI embyropathy have been described. One neonate
had both CA and ACC together with other anomalies26,27;
another neonate had choanal and esophageal atresia with
other severe cardiac and abdominal malformations, and
died from post-surgical infection.27 A neonate with ACC,
esophageal atresia, and facial dysmorphism has also been
reported.28 Another was born with CA, facial dysmorphism,
and developmental delay.29 Of potential significance, one
case report described a neonate who had been exposed
to MMI only after the eighth week of gestation as having
bilateral CA.30 The time of exposure (at eight weeks) is
relatively late in term of embryogenesis.
In a cohort of 36 newborns exposed to MMI in utero,
Wing and colleagues found a rate of major malformations
of 2.7%. They did not identify any cases of scalp defects
or CA.20
Cases with umbilical hernia (n = 1)20,26 and omphalocele
(n = 4)19,26 have been reported after exposure to MMI. Of
note, five sets of twins have been described, and in two
of the sets both twins were identically affected: one set
of twins had ACC and the other had CA. Unfortunately,
zygocity was not reported in all of the twins.6,26,28,31,32
Case–control studies
Two case–control studies investigated an association
between MMI and specific malformations that had been
associated with MMI.7,25 Barbero et al. compared the
incidence of CA in MMI-exposed pregnancies and control
subjects.7 Mothers of cases (n = 61) and control subjects
(n = 183) were interviewed to record sociodemographic
status, obstetrical and genetic history, and exposure to
different agents during pregnancy; specifically, detailed
information regarding hyperthyroidism and MMI intake was
obtained. Prenatal exposure to maternal hyperthyroidism
treated with MMI was identified in 16.4% of cases (10/61)
and only 1.1% (2/183) in the control group (OR 17.75;
95% CI 3.49 to 121.40). Cases and control subjects
did not differ in level of parental education, paternal
occupation, twinning, maternal parity, and other exposures
during pregnancy. Facial features in cases showed some
similarities. These data suggest that prenatal exposure
to maternal hyperthyroidism and treatment with MMI is
associated with CA. In addition, based on their cases and a
critical review of the literature, the authors proposed that
the mother’s disease, and not the treatment with MMI,
might be the causal factor.7
Van Dijke et al. reviewed 49 091 birth records of neonates
with ACC and reported 13 cases of scalp skin defects
(0.03%). None of the mothers of these neonates were
exposed to MMI during pregnancy. Among 24 records of
pregnant women treated with MMI and carbimazole, no
child was affected by ACC.25
Case reports
MMI-related adverse fetal outcomes have been reported
in numerous case reports and case series. Fifteen cases
1080 l NOVEMBER JOGC NOVEMBRE 2012
Propylthiouracil
Several cohort studies of PTU exposure during pregnancy
met our inclusion criteria. A prospective observational
controlled cohort study of PTU-exposed pregnancies in
women counselled by the Israeli Teratology Information
Service between the years 1994 and 2004 involved 115 PTUexposed pregnancies and 1141 control subjects exposed to
non-teratogenic drugs.5 The rate of major anomalies was
comparable between the groups (1.3% for PTU exposure
[1/80] and 3.2% for control subjects [34/1066]; P = 0.5).
Hypothyroidism was found in 9.5% of fetuses or neonates
(56.8% of whom had goitre). Neonatal hyperthyroidism,
possibly resulting from maternal disease, was found
in 10.3%. Goitres diagnosed prenatally by ultrasound
were successfully treated in utero by adjustment of the
maternal dose of PTU. In most cases, neonatal thyroid
function normalized during the first month of life without
treatment. The median birth weight in neonates exposed
to PTU (3145 g, interquartile range 2655 to 3537 g) was
lower than in control subjects (3300 g, interquartile range
2968 to 3600 g) (P = 0.018).
Osorio and colleagues described the management of 19
hyperthyroid pregnant women between 1987 and 1991.33
Of these, 18 had diffuse goitre and one had nodular goitre.
In 10 of the women, thyrotoxicosis preceded pregnancy.
PTU was used in 17 women (7 throughout pregnancy); five
required surgery because of a poor response, one received
propranolol, and one patient was not treated because of
lack of attendance. Caesarean section was performed in 12
women, five had a vaginal delivery, one had a miscarriage at
20 weeks’ gestation because of a neurological malformation,
The Safety of Methimazole and Propylthiouracil in Pregnancy: A Systematic Review
and one patient was lost to follow-up before delivery.
The newborn of the untreated woman had neonatal
thyrotoxicosis, but the remaining 16 neonates did not show
evidence of thyroid dysfunction. Newborns whose mothers
received PTU until delivery had significantly lower reverse
T3 levels and non-significant changes in levels of T4 and T3.
At the end of the observation period, eight women were
euthyroid, three were hypothyroid (2 after 131I treatment
and 1 after surgery), four remained on PTU, and four were
lost to follow-up.
liver impairment appears to be more frequent, with the
prevalence estimated at 1 in 2000 children.15 Despite the
publicity and recommendations that PTU should not be
used in children, at least two children suffered from serious
liver impairment after exposure to PTU: one had liver
failure that required liver transplantation, and the other
had acute liver injury, pending liver failure, that eventually
resolved spontaneously. On April 21, 2010, the FDA
“black box warning” about use of PTU was issued.15 The
FDA made the following recommendations:
Wing and colleagues described 99 cases of gestational
exposure to PTU, with a normal rate of major birth defects
(3%).20
1. PTU should not be prescribed as the first-line
treatment agent in children or adults.
A single case report published in 2011 described ACC in
a surviving twin after in utero PTU exposure. The authors
could not attribute this malformation to a possible vascular
etiology (suggested by a vanishing twin) or to maternal
hyperthyroidism. They concluded that coincidence of
PTU exposure and ACC seems unlikely.34
Neurodevelopmental Effects
Eisenstein and colleagues examined the intellectual capacity
of 31 subjects aged four to 23 years, born to women with
Graves’ disease who received anti-thyroid drugs throughout
pregnancy.24 Fifteen of the subjects were exposed to MMI
(40 to 140 mg/week) and 16 were exposed to PTU (250 to
1400 mg/week). IQ was assessed using the Wechsler test
appropriate for age. Twenty-five unexposed siblings served
as control subjects. The exposed and unexposed groups did
not differ in total IQ. The groups scored equally in verbal and
performance skills and in each of six main sub-categories of
the tests. There was no difference in performance between
subjects exposed to MMI and those exposed to PTU, or
between those exposed to higher doses (> 40 mg of MMI/
week or > 600 mg PTU/ week) and lower doses. All children
were euthyroid at birth and none had goitre. The authors
concluded that exposure to MMI or PTU during pregnancy
in doses sufficient to control maternal hyperthyroidism does
not pose any threat to intellectual capacity in the offspring.
Hepatotoxicity
Over the past 20 years, 22 serious cases of liver injury
(resulting in 9 deaths and 5 liver transplants) have been
reported to the FDA and to the Adverse Event Reporting
System.35 The estimated occurrence of PTU-related acute
liver failure is 1 in 10 000 exposed adults.21 This is believed
to be an immune allergic response that occurs only with
PTU. In severe cases, fatality rates of up to 25% to 50%
have been reported.21 The United Network for Organ
Sharing reported 16 liver transplants performed for PTUrelated liver failure in adults.35 In children, PTU-related
2. However, because of the multiple reports of
MMI teratogenicity, PTU should be prescribed
for hyperthyroidism during the first trimester of
pregnancy, at least until more is known regarding the
teratogenicity of MMI.
3. PTU is recommended in preference to MMI in lifethreatening thyrotoxicosis or thyroid storm because
of its superiority in inhibiting peripheral conversion
of T4 to T3.
4. PTU can be used in individuals who have experienced
adverse responses to MMI (other than agranulocytosis)
and for whom radioiodine or surgery are not treatment
options.35
Although hepatotoxicity in adults and children is well
documented, there are limited data regarding hepatotoxicity
in pregnant women and even fewer regarding effects on the
fetus, leading to conflicting opinions. We identified two case
reports of hepatotoxicity in pregnant women with Graves’
disease, one of them requiring a liver transplant and the
other having resolution after discontinuation of PTU.36,37
In June 2012, we encountered a third case in Toronto
(unpublished case). In neonates, the most significant case
described neonatal hepatitis that was positive for newborn
lymphocyte transformation test for PTU.38 This test suggests
an immunological reaction to PTU through lymphocytes.
This case describes prenatal exposure to PTU given for
maternal Graves’ disease.38 On the basis of the positive
lymphocyte test, the authors concluded that this was a clear
case of neonatal PTU-induced hepatotoxicity.
Less obvious cases were reported by Hare and Kitzmiller
in five pregnant women with both Graves’ disease and
juvenile diabetes who were treated with PTU.39 Four of
the infants had hyperbilirubinemia, which might have been
attributed to prenatal PTU exposure but might also have
indicated liver impairment due to the underlying diabetes.
In contrast, Devi et al. reported a case of hyperthyroidism
NOVEMBER JOGC NOVEMBRE 2012 l 1081
Drugs in Pregnancy
Details of papers included in the systematic review
Drugs, daily dose, and timing of exposure
during pregnancy
Major related malformations
(ACC, CA, EA embryopathy,
liver abnormalities)
MMI 10 to 1680 mg 1st trimester
None
1. Malformation of ear lobe > 10 weeks
2. Omphalocele
N/A
None
1. Severe pulmonic stenosis
2. Ventricular septal defect
3. Patent ductus arteriosus
N/A
None
Congenital inguinal hernia NS
Barbero et al.
(N = 61)
Case–control for CA
(N = 12)
MMI 20.5 mg
CA-10
10/61 vs.2/183, OR 17.75,
95% CI (3.49 to 12.4)
N/A
Rosenfeld et al.5
(N = 115)
PTU 150 mg (100 to 200 mg)
98 treated throughout pregnancy
15 treated from start of 2nd trimester
2 treated from start of 3rd trimester
None
1. Hip dysplasia NS
2. Low birth weight (3145 vs. 3300 g)
3. Hypothyroidism 9.5%
Osorio et al.33
(N = 19)
PTU used in 17 women, 7 throughout
the entire pregnancy
None
PTU treated had lower rT3 levels.
Eisenstein et al.24
(N = 31)
MMI = 15
PTU = 16
MMI 40 to 140 mg/week
ACC minor × 2
1. Anal atresia
Mujtaba and Burrow23
(N = 26)
PTU 100 to 400 mg
None
Thyrotoxicosis (2), mild thyrotoxicosis and
small goitre (1), aortic atresia: infant death
MMI 15 mg throughout pregnancy
Case 1. ACC
Imperforated anus
MMI 15 mg 1st trimester, and then 5 mg
throughout pregnancy
Case 2. ACC
None
MMI10 mg until 8 weeks, then
PTU 200 mg until delivery
Case 1. CA and ACC
Umbilical hernia, pilonidal sinus,
limb hypertonia
MMI 40 to 20 mg throughout pregnancy
Case 2. dizygotic twins:
ACC/None
Small omphalocele
None
Iwayama et al.32
(N = 2)
MMI 15 to 30 mg/kg/day
Monozygotic twins:
ACC/none
Karg et al.46
(N = 1)
MMI 150 g/day then PTU from 6 weeks
until delivery
ACC
Facial dysmorphism
Barbero et al.7
(N = 3)
MMI 15 mg throughout pregnancy
Case 1. twins
CA/CA
A. Facial dysmorphism
B. Facial dysmorphism (same)
MMI 20 mg throughout pregnancy
CA
Facial dysmorphism (similar)
Micrognathia
Nakamura et al.47
(N = 1)
MMI 10 mg 1st trimester
ACC bilateral
N/A
Valdez et al.48
(N = 1)
MMI 50 g 1st trimester, and then 30 mg
until delivery
Embryopathy
Clementi et al.17
(N = 1)
MMI 20 mg until 6 weeks, then PTU till
delivery
CA
Ozgen et al.49
(N = 1)
MMI in the first 3 months of pregnancy
CA
Embryopathy
Hall50
(N = 1)
MMI in the first 2 months of pregnancy
PTU for last 7 months of pregnancy
CA
Facial dysmorphism
Milham and Ellege31
(N = 3)
N/A
Case 1. twins
ACC/ACC
Case 2. ACC
N/A
Study and
sample size
Momotani et al.
(N = 243)
19
Wing et al.20
(N = 135)
PTU = 99
MMI = 36
7
Ferraris et al.26
(N = 3)
Pregnancy and neonatal outcome
PTU 250 to 1400 mg/week
Facial dysmorphism
Ear malformation
Hypertonia
Continued
1082 l NOVEMBER JOGC NOVEMBRE 2012
The Safety of Methimazole and Propylthiouracil in Pregnancy: A Systematic Review
Continued
Major related malformations
(ACC, CA, EA embryopathy,
liver abnormalities)
Study and
sample size
Drugs, daily dose, and timing of exposure
during pregnancy
Greenberg
(N = 1)
MMI
CA
Embryopathy
Van Dijke et al.25
(N = 1)
MMI 20 mg throughout pregnancy
Thyroid hormone extract 50 mg
CA
Johnsson et al.27
(N = 1)
MMI 30 mg until 18 weeks partial
thyroidectomy
Metoprolol 150 mg stopped at 5 weeks
CA, EA
Mandel and Cooper14
(N = 1)
MMI 30 to 90 mg until 20 weeks partial
thyroidectomy
ACC
Vogt et al.51
(N = 1)
MMI 40 mg until 12 weeks, then reduced
to 20 mg
ACC
Farine et al.52
(N = 1)
MMI 10 mg until confirmation of
pregnancy and then switched to PTU
ACC
Gripp et al.28
(N = 3)
15 mg MMI until 6 weeks, then nothing
for 4 weeks, switched to PTU 50 mg at
10 weeks plus propranolol dose
Thyroidectomy 16 weeks
Fluoxetine
EA
Multiple area ACC
Facial dysmorphism
Clinodactyly
Sensorineural hearing loss
MMI 40 mg decreased to 10 mg at
36 weeks due to hypothyroidism
Propranolol 60 mg
Twins
A. CA
Facial dysmorphism, ear abnormality,
clinodactyly, single palmar crease, 46XX
B. Facial dysmorphism
Kim et al.21
(N = 1)
MMI during first 9 weeks
ACC
del Cacho and Frias30
(N = 1)
Methimazole 10 mg/day from 8th week
Bil CA
Facial dysmorphism
Ono et al.53
(N = 1)
MMI used during pregnancy
None
Omphalocele
Morris et al.34
(N = 1)
PTU till 25 weeks gestation
Maternal fulminant hepatic
failure encephalopathy,
coagulopathy.
Coma-thyrotoxicosis
Liver transplant
Post transplant Caesarean section at
26 weeks
IUGR
Stillbirth
Parker37
(N = 1)
PTU 450 mg until 20 weeks
Hepatitis
Switched to propranolol and then
MMI 15 mg with resolution
Thyrotoxic
Non-viral hepatitis Resolution
after discontinuation of the
PTU.
Positive lymphocyte
transformation test for PTU
(negative for MMI)
N/A-assuming uneventful.
Hayashida et al.38
(N = 1)
PTU 250 mg/day
Methyldopa 250 mg/daily
Propranolol 80 mg/daily until 30 weeks
Thyrotoxic
Neonatal hyperthyroidism,
Non-viral hepatitis. Positive lymphocyte
transformation test for PTU
Lollgen et al.54
(N = 1)
PTU used during pregnancy
ACC in surviving twin
Co-twin demise
29
Pregnancy and neonatal outcome
None
Preterm labour at 27 weeks,
tracheoesophageal fistula omphalocele,
multiple ventricular septal defects
Infant death from post-surgical infection
EA: esophageal atresia
NOVEMBER JOGC NOVEMBRE 2012 l 1083
Drugs in Pregnancy
in pregnancy in which the mother was treated with PTU
and developed maternal hepatitis.40 The fetal liver was
not affected. From this single case, Devi et al. concluded
that PTU-induced fetal hepatitis is an extremely rare side
effect that should not affect the mode of therapy. As both
PTU and MMI cross the placenta and are detected in the
fetal circulation,13 it seems that PTU treatment should be
discontinued after the first trimester of pregnancy, given
the high probability of PTU toxicity in children and one
reported case of newborn liver impairment.38
Data Synthesis
The present systematic literature review included published
studies evaluating the outcome of prenatal exposure to
MMI and PTU. MMI exposure was mostly associated
with ACC15 and CA.23 Because of the rare occurrence of
these malformations, most cohort studies (each containing
several hundred cases) could not detect them.19–20,22–24
In contrast, a case–control study clearly delineated
the contribution of MMI to cases of CA.7,25 A similar
case–control study has failed to prove an association
between MMI and ACC7; ACC is an anomaly that occurs
at a rate of 1:20 000, an extremely low absolute risk,
despite having a high odds ratio of 17.7 These principles
are important in counselling women taking MMI.
Rosenfeld et al. predicted that 20 cases of ACC should
occur in 100 million births, based on an incidence of
ACC of 0.05% and an incidence of hyperthyroidism in
pregnancy of 0.2%.5 Approximately one third of these are
treated with MMI.41
It is important to consider that uncontrolled maternal
hyperthyroidism per se may theoretically cause congenital
malformations and adverse pregnancy outcome. Momotani
et al. reported that treatment of maternal hyperthyroidism
with either PTU or MMI was associated with a reduced
rate of congenital malformations.19 Their study included
643 neonates born to mothers with Graves’ disease
and reported a 6% rate of congenital malformations
in mothers with uncontrolled hyperthyroidism, much
higher than in the PTU and MMI-treated groups. In a
case–control study, Barbero et al. were unable to attribute
the higher rate of CA to either MMI exposure or to
maternal hyperthyroidism.7 In fact, these authors raised
the suspicion that this malformation may be attributed to
the underlying hyperthyroidism and not to MMI exposure;
their suspicion was based on the fact that exposure to
MMI was relatively late in pregnancy (at 28 weeks in one
of their 10 cases), and not during the critical embryogenic
period earlier in pregnancy (4 to 10 weeks). However, in
most cases with MMI-associated embryopathy in the case
reports we reviewed, the exposure to MMI did indeed
1084 l NOVEMBER JOGC NOVEMBRE 2012
occur in the first trimester during the critical embryogenic
period, and occurred mostly in mothers with uncontrolled
thyrotoxicosis. The fact that CA has been documented with
PTU exposure only once provides strong evidence that it is
not the hyperthyroid status itself but MMI exposure that is
the cause of embryopathy.
Although it is still debatable whether the rates of some of
MMI-related malformations are above the baseline risk in
the general population, or may be related to hyperthyroidism
per se, these adverse outcomes have not been reported in
association with PTU treatment. From a clinical practice
perspective, the MMI-related malformations can have
serious health implications. The possible teratogenic effect
of MMI therefore cannot be ignored, and use of the drug
should be avoided in the first trimester of pregnancy.
There is significantly less available evidence for potential
teratogenicity with use of PTU. In cohort studies we found
no evidence of an increased risk of fetal malformations.
Although a few cases of transient neonatal hypothyroidism
and low birth weight have been reported,5 these are
not considered to be of significant clinical relevance.
Based upon the available cohort studies, and the lack of
homogenous case reports, it is conceivable that PTU is not
a human teratogen. However, a major concern regarding
PTU treatment arises from its emerging potential for
serious hepatotoxicity.
Both MMI and PTU have been shown to cause
agranulocytosis,42,43 and both drugs can cause fever and
arthralgia.44 Importantly, both drugs, when administered at
high doses, can cause fetal and neonatal hypothyroidism;
therefore, vigilant monitoring of maternal thyroid function
and of sonographic signs of fetal hypothyroidism is
warranted.45
CONCLUSION
Our systematic review has provided reasonable evidence
that MMI has rare but clinically significant teratogenic
effects when the fetus is exposed to the drug in the
first trimester, and that PTU has potential for severe
hepatotoxic sequelae. Thus, it is reasonable to recommend
that in pregnant women with hyperthyroidism, PTU should
be administered during the first trimester and switched
thereafter to MMI for the remainder of the pregnancy.
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